Shusuke Uchida

Serological aggravation of autoimmune thyroid disease in two cases receiving nivolumab.

Nivolumab, a blockade of programmed cell death 1, is now administrated for advanced malignant melanomas. Nivolumab‐associated adverse events include organ‐specific autoimmune disorders; autoimmune thyroid disease, vitiligo and insulin‐dependent diabetes. However, predisposed persons are currently unknown. Here, we report serological aggravation of autoimmune thyroid disease in two cases receiving nivolumab: one with Hashimoto disease and another with probable subclinical Hashimoto disease. We should verify if nivolumab‐related hypothyroidism and hyperthyroidism are predisposed to occur in euthyroid individuals with subclinical autoimmune thyroid disease.

Paraneoplastic pemphigus associated with Castleman disease: Progression from mucous to mucocutaneous lesions with epitope-spreading phenomena

Paraneoplastic pemphigus (PNP) is a frequently fatal autoimmune blistering disease of the skin and mucous membranes.1 PNP is commonly associated with malignant neoplasms or haematological disorders like Castleman disease (CD). The eruptions may resemble those seen in various other conditions such as lichen planus (LP), graft-versus-host disease, erythema multiforme (EM), bullous pemphigoid and pemphigus vulgaris (PV).2 This article is protected by copyright. All rights reserved.

Bullous pemphigoid associated with psoriasis: A possible example of an inverse intramolecular epitope-spreading phenomenon.

Dear Editor, An 82-year-old Japanese man with a 40-year history of psoriasis was referred to us, because small tense bullae first appeared on the bilateral legs, and then spread over the whole body. Physical examination revealed small tense bullae on the normal skin and the scaly erythematous psoriatic lesions (Fig. 1a,b). Mucous membranes were not involved. Laboratory examinations showed increased leukocytes (10,000/lL; normal, 3900–9300/lL) with normal eosinophils (0.6%; normal, 0.2–4.1%) and normal C-reacted protein (0.042 mg/dL; normal, <0.3 mg/dL). An index in enzyme-linked immunosorbent assay (ELISA) was faintly positive for the recombinant protein (RP) of the BP180-NC16a domain (16.1; normal, <9), whereas indexes were negative for the RP of BP230, desmoglein 3, desmoglein 1 and type VII collagen. A biopsy taken from a bulla on the normal skin showed blister formation, infiltration of eosinophils and neutrophils in the blister, and mononuclear cells in the upper dermis (Fig. 1c), while another biopsy from a psoriatic lesion revealed hyperkeratosis, parakeratosis, acanthosis and Munro’s microabscess in the horny layer (Fig 1d). Direct immunofluorescence (IF) showed linear depositions of immunoglobulin (Ig)G and C3 in the basement membrane zone (BMZ). Indirect IF using normal human skin revealed circulating IgG anti-BMZ autoantibodies at 1:160 dilution (Fig. 1e), which reacted with the epidermal side of 1 mol/L NaCl-split normal human skin at 1:10 dilution (Fig. 1f). In immunoblotting of concentrated culture supernatant of HaCaT cells, IgG antibodies in the patient serum reacted with linear IgA dermatosis antigen-1 (LAD-1) (Fig. 1g). There was no reactivity with the recombinant proteins of NC16a and C-terminal domains of BP180, normal human dermal extract or purified human laminin-332. Intravenous prednisolone 30 mg/day and subsequent 70 mg/day did not suppress progress of blister formation, whereas topical calcipotriol and betamethasone butyrate propionate were moderately effective for psoriasis. Then, the patient was treated with i.v. Ig 400 mg/kg per day for 5 days consecutively from day 19. The treatment suppressed new blister formation. Subsequently, betamethasone 6 mg/day was administrated, and tapered. The ELISA indexes of the BP180NC16a domain RP were 19.5 at day 24 and 3.6 at day 52.

Refractory bullous pemphigoid leaving numerous milia during recovery

Recovery with milia may occur in bullous pemphigoid (BP), mucous membrane pemphigoid (MMP) and epidermolysis bullosa acquisita (EBA). Scarring commonly occurs in MMP and EBA. Here, we report a 62‐year‐old man patient with BP, who was left with numerous milia during recovery. The patient had immunoglobulin (Ig)G autoantibodies to the recombinant protein of the BP180‐NC16a domain and the soluble 120‐kDa ectodomain of BP180 (linear IgA bullous dermatosis [LAD]‐1). There are cases of BP with IgG autoantibodies to LAD‐1 and/or the recombinant protein of BP180 C‐terminal domain. Extensive milia formation during recovery may be associated with immunological predisposition and/or improper interaction between hemidesmosomes and the extracellular matrix components.

Mucous Membrane Pemphigoid with IgG Autoantibodies to the 120-kDa Ectodomain of Type XVII Collagen (BP180/Linear IgA Dermatosis Antigen) in a Patient with Idiopathic Thrombocytopenic Purpura

© 2015 The Authors. doi: 10.2340/00015555-1964 Journal Compilation

Patch test reaction to p-phenylenediamine can persist for more than 1 month

A 61-year-old man was referred to us with pruritic eruptions on the upper back in January 2013. The patient had used a hair-dye for 12 years. The patient had felt a recurring pruritic sensation of the scalp after using the hair-dye for several months previously. Pruritic eruptions on the scalp and the upper back had occurred together with general fatigue 1 day after use of the hair-dye in December 2012. Betamethasone valerate 0.12% lotion and diflucortolone valerate 0.1% ointment had been applied on the scalp and the upper back, but pruritic eruptions had been persistent on the back. Physical examination at the initial examination revealed pruritic erythematous macules on the upper back (Fig. 1a). Difluprednate 0.05% ointment was applied on the affected lesions. The eruptions ceased 2 weeks later. Patch testing (International Contact Dermatitis Research Group criteria; Finn Chambers® on Scanpor®

Cellulitis with Leukocytopenia as an Initial Sign of Acute Promyelocytic Leukemia

Patients with hematologic malignancies are immunosuppressive and may develop cutaneous or invasive infections as a primary sign of immune suppression. Acute promyelocytic leukemia (acute myeloid leukemia M3) is caused by translocation of reciprocal chromosomal rearrangement t(15;17), which produces an oncogenic protein. We herein describe a 71-year-old man having cellulitis with leukocytopenia as a first sign of acute promyelocytic leukemia. Dermatologists and hematologists should keep in mind that patients with a hematologic malignancy, such as acute promyelocytic leukemia, can develop cellulitis with leukocytopenia.

Paraneoplastic pemphigus presenting lichen planus-like lesions

patch test was recommended but he refused. He did not want topical immunotherapy inducing an allergic response. Therefore, tofacitinib 5 mg twice daily was prescribed. After 1 month, hair growth first began at the area of contact dermatitis; this became more conspicuous after 2 months (Fig. 1b). After 5 months, complete regrowth was achieved (Fig. 1c) and was well-maintained during 4 additional months of tofacitinib administration. Then, the patient was lost to follow up. There is some evidence that contact dermatitis can help to treat AA. For example, the therapeutic effect of allergic contact dermatitis (ACD) from diphenylcyclopropenone on AA is wellknown. Similarly, ACD from wig adhesive tape demonstrated an incidental therapeutic effect on AA. Antigenic competition and alteration of the cytokine milieu during the resolution of ACD may ameliorate the follicular autoimmune reaction. A recent gene-level study supported this: negative immune regulation transcripts showed greater relative expression than activation transcripts during the resolution of ACD. These targets may be modulated by RNA interference to promote hair growth. Irritant contact dermatitis (ICD) can also induce hair growth in AA (e.g. anthralin), but its mechanism is less clear. Although early stage ACD is distinguished from ICD by the presence of a sensitization phase, later stage ACD in the elicitation phase manifests similarly to ICD, sharing cytokines and chemokines. Moreover, regulatory cytokines are produced to limit inflammation during repeated irritant application, which may regulate the autoimmune process of AA. Notably, either contact dermatitis or tofacitinib alone might have improved AA. However, we suspect that tofacitinib and contact dermatitis acted synergistically to restore hair growth because hair began to grow from the area of contact dermatitis only after tofacitinib administration. Tofacitinib significantly downregulates genetic expression of various pro-inflammatory mediators in the affected skin. Therefore, immune downregulation with tofacitinib might have acted as an RNA interference signal, encouraging the inhibition of follicular autoimmune reactions during the resolution of contact dermatitis. The reverse interaction is also plausible. Interestingly, we detected a similar phenomenon, wherein tofacitinib caused more rapid hair growth within psoriatic plaques in an AA patient with psoriasis. Unfortunately, we could not define the nature of the contact dermatitis because the patient refused a patch test. Although silicone is generally known as an inert material, several case reports of silicone-induced ACD exist. However, ICD is also possible because the lesion was limited to the contact site. To our knowledge, this is the first case report of the synergistic effect of contact dermatitis and oral tofacitinib in AA. Further accumulation of cases is necessary to elucidate details of their synergistic effects and mechanism of inducing hair growth.

Cutaneous leishmaniasis caused by Leishmania tropica in Israel

Dear Editor, Cutaneous leishmaniasis (CL) is caused by the vector-borne protozoan parasite Leishmania and is transmitted via infected female sandflies. A 22-year-old man with Israeli and Japanese parents presented with ulcerative eruptions in June 2017. His business was in Israel but he occasionally traveled to Japan. He noticed skin lesions when in Israel in September 2016. Physical examination revealed peripherally ridged, centrally ulcerative erythematous nodules, 27 mm 9 17 mm and 21 mm 9 16 mm in size, on the right forearm (Fig. 1a). Abnormal general symptoms were absent. Laboratory examinations revealed 8890/lL leukocytes, 5.4% eosinophils, 15.8 g/dL hemoglobin and 26.0 9 10/lL platelets. Biopsy showed diffuse infiltration of inflammatory cells including lymphocytes, plasma cells and monocytes in the dermis (Fig. 1b,c). Leishmania amastigotes could not be found at high magnification in hematoxylin–eosin (HE) staining but Giemsa staining of a biopsy tissue-crimping specimen detected a small number of them (arrows) (Fig. 1d,e). For molecular diagnosis of Leishmania infection, DNA was extracted from the skin biopsy sample using a DNeasy Blood and Tissue Kit (QIAGEN, Tokyo, Japan). We performed polymerase chain reactions (PCR) with DNA samples to identify the Leishmania large subunit ribosomal RNA gene and Leishmania kinetoplastid membrane protein-11 gene, and detected products with expected sizes on agarose gel electrophoresis. For genotyping of the Leishmania species, PCR targeting internal transcribed spacer (ITS) was performed with patientderived DNA samples, and the PCR products were sequenced after cloning into the pCR2.1-TOPO vector using a TOPO TA Cloning Kit (Thermo Fisher Scientific, Yokohama, Japan). Analysis of the sequence using the neighbor-joining method determined the species was clustered in the Leishmania tropica clade. Based on these findings, we diagnosed the ulcerative eruptions as CL.

Malignant Melanoma on a Thermal Burn Scar with an Interval of More Than 70 Years

Cases of malignant melanoma on thermal burn scars have occasionally been reported. We report a 78-year-old Japanese female with malignant melanoma on a thermal burn scar with an interval of more than 70 years. Our case reemphasizes the importance of regular examinations in persons with thermal burn scars.